Can we discover pharmacological promiscuity early in the drug discovery process?

被引：64

作者：

Peters, Jens-Uwe ^{[1
]}

Hert, Jerome ^{[1
]}

Bissantz, Caterina ^{[1
]}

Hillebrecht, Alexander ^{[2
]}

Gerebtzoff, Gregori ^{[2
]}

Bendels, Stefanie ^{[2
]}

Tillier, Fabien ^{[3
]}

Migeon, Jacques ^{[4
]}

Fischer, Holger ^{[2
]}

Guba, Wolfgang ^{[1
]}

Kansy, Manfred ^{[2
]}

机构：

[1] F Hoffmann La Roche Ltd, pRED, Pharma Res & Early Dev, Discovery Chem, CH-4070 Basel, Switzerland

[2] F Hoffmann La Roche Ltd, pRED, Pharma Res & Early Dev, Nonclin Safety, CH-4070 Basel, Switzerland

[3] Cerep SA, Bois Eveque, F-86600 Celle Levescault, France

[4] Cerep Inc, Redmond, WA 98052 USA

来源：

DRUG DISCOVERY TODAY | 2012年 / 17卷 / 7-8期

关键词：

SAFETY PHARMACOLOGY; PHYSICOCHEMICAL PROPERTIES; PRIVILEGED STRUCTURES; MOLECULAR COMPLEXITY; RECEPTOR; DESIGN; LIPOPHILICITY; INHIBITORS; EFFICACY; BINDING;

D O I：

10.1016/j.drudis.2012.01.001

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The term 'pharmacological promiscuity' describes the activity of a single compound against multiple targets. When undesired, promiscuity is a major safety concern that needs to be detected as early as possible in the drug discovery process. The analysis of large datasets reveals that the majority of promiscuous compounds are characterized by recognizable molecular properties and structural motifs, the most important one being a basic center with a pK(a)(B) > 6. These compounds interact with a small set of targets such as aminergic GPCRs; some of these targets attract surprisingly high hit rates. In this review, we discuss current trends in the assessment of pharmacological promiscuity and propose strategies to enable early detection and mitigation.

引用

页码：325 / 335

页数：11

共 87 条

[11] Recognition of privileged structures by G-protein coupled receptors [J].

Bondensgaard, K ;

Ankersen, M ;

Thogersen, H ;

Hansen, BS ;

Wulff, BS ;

Bywater, RP .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (04) :888-899

[12] Small kinase assay panels can provide a measure of selectivity [J].

Brandt, Peter ;

Jensen, Annika Jenmalm ;

Nilsson, Jonas .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (20) :5861-5863

[13] Cross-Pharmacology Analysis of G Protein-Coupled Receptors [J].

Brianso, Ferran ;

Carrascosa, Maria C. ;

Oprea, Tudor I. ;

Mestres, Jordi .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2011, 11 (15) :1956-1963

[14] 1-[2-[(heteroaryloxy)heteroaryl]carbamoyl]indolines:: Novel and selective 5-HT2C receptor inverse agonists with potential as antidepressant/anxiolytic agents [J].

Bromidge, SM ;

Dabbs, S ;

Davies, S ;

Duckworth, DM ;

Forbes, IT ;

Jones, GE ;

Jones, J ;

King, FD ;

Saunders, DV ;

Blackburn, TP ;

Holland, V ;

Kennett, GA ;

Lightowler, S ;

Middlemiss, DN ;

Riley, GJ ;

Trail, B ;

Wood, MD .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2000, 10 (16) :1863-1866

[15]

Car B.D., 2012, POLYPHANNACOLOGY DRU, P9

[16] A chemogenomic approach to drug discovery: focus on cardiovascular diseases [J].

Cases, Montserrat ;

Mestres, Jordi .

DRUG DISCOVERY TODAY, 2009, 14 (9-10) :479-485

[17] Exploratory Safety Pharmacology: a new safety paradigm to de-risk drug candidates prior to selection for regulatory science investigations [J].

Cavero, Icilio .

EXPERT OPINION ON DRUG SAFETY, 2009, 8 (06) :627-647

[18] Towards triple vasopeptidase inhibitors for the treatment of cardiovascular diseases [J].

Daull, Philippe ;

Jeng, Arco Y. ;

Battistini, Bruno .

JOURNAL OF CARDIOVASCULAR PHARMACOLOGY, 2007, 50 (03) :247-256

[19] Inhibition of Zinc Metallopeptidases in Cardiovascular Disease - From Unity to Trinity, or Duality? [J].

Dive, Vincent ;

Chang, Cheng-Fu ;

Yiotakis, Athanasios ;

Sturrock, Edward D. .

CURRENT PHARMACEUTICAL DESIGN, 2009, 15 (31) :3606-3621

[20] Privileged structures: A useful concept for the rational design of new lead drug candidates [J].

Duarte, Carolina D. ;

Barreiro, Eliezer J. ;

Fraga, Carlos A. M. .

MINI-REVIEWS IN MEDICINAL CHEMISTRY, 2007, 7 (11) :1108-1119

← 1 2 3 4 5 6 7 8 9 →